Mammalian CELF/Bruno-like RNA-binding proteins: molecular characteristics and biological functions
Introduction
RNA-binding proteins are the cog-wheels of molecular machines that regulate gene expression at the post-transcriptional level. As cog-wheels they interact with other proteins and transmit specific packets of information. However, they do not always fulfil exclusive functions and according to their localisation certain can enter into different molecular machineries that ensure different functions.
The CELF and Bruno-like families of RNA-binding proteins each contain six members of which five are common. These proteins are related both structurally and by sequence similarity. Due to alternative splicing, several isoforms of certain members have been identified and it can be foreseen that the genes encoding all the family members probably produce several isoforms. Although some studies indicate a certain functional redundancy, the different members have distinctive, but also overlapping, expression patterns.
Different members of the CELF/Bruno-like protein families have been shown to be implicated in two major biological processes situated either in the nucleus or in the cytoplasm. The major identified nuclear function is a regulatory role in the alternative splicing of target pre-mRNAs. CELF/Bruno-like family members are also implicated in the control of translation and mRNA stability that are cytoplasmic events. Again several mRNA targets have been identified.
The aim of this review is to present a synthetic picture of the current state of our knowledge relative to the functional roles of the CELF family of proteins. This should enable researchers working on similar gene products or in related fields to better apprehend the functional interest of this family of RNA-binding proteins. Furthermore, it will highlight some important questions that still need to be resolved.
Section snippets
Family members
The founder members of the CELF family are CUG-BP1 (CELF1) [1] and ETR-3 (CELF2) [2] and that of the Bruno-like (BRUNOL) family is the Drosophila protein Bruno [3]. Since, other members have been identified mainly by sequence similarity. In fact, the founder members were cloned or identified in a number of laboratories which has lead to a profusion of names and the separate naming systems.
The purification and cloning of CUG-BP1 [1] was based on the capacity of this protein to bind to a (CUG)8
Gene expression patterns and localisation
Analysis of the published data [5], [7], [9] and data base searches clearly establish that the primary transcripts of several of the CELF genes are subject to alternative splicing. To date four protein isoforms are known for the human CELF1/CUG-BP1 (Accession numbers: AAH36782; Q92879/AAF86230/AAF78955/CAC20566; AAC50895/NP_006551; AAH31079/NP_941989/AAF78956) and seven for the human CELF2/CUG-BP2 (AAK92699/AAD02074; AAK72224; NP_006552; AAB09040; AAH36391; AAK72223; AAD13760). The
Functional roles of CELF proteins
Most of the functional data for the CELF proteins have been obtained with either the CELF1 or CELF2 family members. Functional data for the other CELF proteins are less abundant. The CELF1/CUG-BP1 protein is localised both in the cytoplasm and the nucleus [1], [11]. For CELF2/CUG-BP2 both nuclear localisation and exports signals have been identified so that the equilibrium between these two cellular compartments could depend on a cell's environmental context [12]. These dual locations also
Acknowledgements
The work performed in the authors' laboratory was supported by grants from ARC (HBO no. 9529; LP no. 4791), the French Ministry of Research BCMS ACI no. 314, and the LRCC (Bretagne) and the AFM.
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